This is the third competing renewal of our Program Project Grant, "Drugs of Abuse: Role of Protein Phosphorylation" (DA010044), which was initially funded in 1996 and most recently in 2006. The grant has been highly successful based on research productivity and initiation of new research projects. The overall objective of the Program Project Grant remains the same as the original, namely, to elucidate the molecular basis of the actions of drugs of abuse, particularly psychostimulants, in the dorsal striatum and nucleus accumbens. The Program Project Grant is organized into three Projects, a Scientific Core and an Administrative Core. The Administrative Core will support the integration of the researchers and institutions involved in the Program Project Grant. The main goal of the Scientific Core is to provide research and technical support for all of the Projects. Responsibilities of the Scientific Core will include the creation, characterization, and breeding of genetically altered animals;the design and execution of yeast two-hybrid studies;the production and maintenance of key reagents stocks and new reagents;and the performance of certain routine tasks required to accomplish the studies described in Projects 1-3. Project 1, "Cell type- and region-specific studies of psychostimulants and dendritic spines" will focus on the role of Cdk5 and WAVE1, regulators of actin dynamics in the dendritic spines. Project 2, "The role of the mGluR5/CK1-CK2/DARPP-32 pathway in mediating the effects of psychostimulants," will extend previous studies of novel signaling pathways that regulate DARPP-32 function. Project 3, "Striatal Phosphoproteins and the Actions of Psychostimulants," which will be a subcontract carried out at Yale University School of Medicine, will study the role of Rap GTPase, and its modulators Rap1GAP and Epac2 in the actions of psychostimulants, as well as study the role of novel isoforms of PP2A in the actions of psychostimulants. Results from the three Projects will complement each other. In addition, there will be a significant level of collaboration between the three Projects, as well as close interaction of the three Projects with the Scientific Core. PUBLIC HEALTH RELEVANCE: Together the three Projects of the Program Project Grant will carry out innovative research that will lead to elucidation of the molecular pathways through which drugs of abuse act in the brain, and to an increased likelihood that therapeutic agents will be developed that will prevent or reverse molecular adaptations within these pathways.